Inhibitory Effects of Ketamine on Lipopolysaccharide-Induced Microglial Activation

Abstract

Microglia activated in response to brain injury release neurotoxic factors including nitric oxide (NO) and proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Ketamine, an anesthetic induction agent, is generally reserved for use in patients with severe hypotension or respiratory depression. In this study, we found that ketamine (100 and 250 μM) concentration-dependently inhibited lipopolysaccharide (LPS)-induced NO and IL-1β release in primary cultured microglia. However, ketamine (100 and 250 μM) did not significantly inhibit the LPS-induced TNF-α production in microglia, except at the higher concentration (500 μM). Further study of the molecular mechanisms revealed that ketamine markedly inhibited extracellular signal-regulated kinase (ERK1/2) phosphorylation but not c-Jun N-terminal kinase or p38 mitogen-activated protein kinase stimulated by LPS in microglia. These results suggest that microglial inactivation by ketamine is at least partially due to inhibition of ERK1/2 phosphorylation.

Ketamine Alleviates Depressive-Like Behaviors <i>via</i> Down-Regulating Inflammatory Cytokines Induced by Chronic Restraint Stress in Mice

“…13,38) In the present study, we show that the CRS-induced activation of TLR4/p38 MAPK signaling pathway is suppressed by ketamine treatment, which further support our hypothesis that ketamine's anti-inflammatory effects contributed to its antidepressive action.…”

“…12,32) Previous studies reporting inhibitory effects of ketamine on lipopolysaccharide (LPS)-induced microglia activation suggested ketamine's inflammatory modulating effects may partly contributed to the beneficial effects of ketamine on depressive symptoms, which is consistent with our findings in animal models. 12,13) As shown in our results, infusion of ketamine significantly decreased the numbers of reactive microglia cells in hippocampus, which is associated with the down-regulation of the pro-inflammatory cytokines.…”

“…[13][14][15] However, little attention has been paid to the role and mechanism of ketamine's antiinflammatory actions in the antidepressant effects following chronic stress exposure. In the present study, we hypothesized that inhibition of microglia activation and down-regulation of pro-inflamatory cytokines contribute to ketamine's rapid antidepressant effects.…”

The role of the surface on microglia function: implications for central nervous system tissue engineering

“…Cell culture media from cells activated with lipopolysaccharide (LPS, 100 ng ml 21 , 3 h; Sigma-Aldrich) was also analysed to serve as the positive control for microglia activation [30].…”

Microglial Ca2+-Activated K+Channels Are Possible Molecular Targets for the Analgesic Effects ofS-Ketamine on Neuropathic Pain

“…Chang et al (2009) reported that ketamine suppresses hyperactivation of cultured microglia stimulated with lipopolysaccharide (LPS). Furthermore, there is emerging evidence that reactive microglia express NMDA receptor subunits (Daulhac et al, 2011;Murugan et al, 2011), thus suggesting that the microglial NMDA receptor is a potential pharmacological target of ketamine.…”